Substituted phenylacetic acid compounds

ABSTRACT

ALPHA,ALPHA - DI - (M-CHLORO - P - CYCLOHEXYLPHENYL)ALPHA,ALPHA&#39;&#39;-DITHIODIACETIC ACID AND ITS DIETHYLAMMONIUM SALT ARE DISCLOSED AND HAVE A HIGH ANTI-INFLAMMATORY, ANALGESIC, AND ANTIPYRETIC ACTIVITY, LOW TOXICITY, AND/OR A FAVORABLE THERAPEUTIC INDEX WITH MINOR OR NO SIDE-EFFECTS.

United States Patent 3,825,587 SUBSTITUTED PHENYLACETIC ACID COMPOUNDSJulius Diamond, Lafayette Hill, and Norman J. Santora, Roslyn, Pa.,assignors to William H. Rorer, Inc., Fort Washington, Pa.

No Drawing. Original application May 5, 1970, Ser. No. 34,870. Dividedand this application Mar. 10, 1972, Ser.

Int. Cl. C07c 63/00 US. Cl. 260501.16 2 Claims ABSTRACT OF THEDISCLOSURE Alpha,alpha di (m-chloro p cyclohexylphenyl)-alpha,alpha'-dithiodiacetic acid and its diethylammonium salt aredisclosed and have a high anti-inflammatory, analgesic, and antipyreticactivity, low toxicity, and/or a favorable therapeutic index with minoror no side-effects.

This is a division of application Ser. No. 34,870 filed May 5, 1970.

BACKGROUND OF THE INVENTION (1) Field of the invention (2) Descriptionof the prior art A number of substituted phenylacetic acids and theiresters have been tested for their anti-inflammatory, analgesic,antipyretic properties but none of them have been accepted by themedical profession for the treatment of humans or have been marketed bythe pharmaceutical industry.

SUMMARY OF THE INVENTION It is one object of the present invention toprovide novel and valuable substituted phenylacetic acid compounds ofhigh anti-inflammatory, analgesic, and antipyretric activity, lowtoxicity and/or a favorable therapeutic index with considerably reducedside-effects.

Another object of the present invention is to provide simple andeiTective processes of making such novel and valuable substitutedphenylacetic acid compounds.

Still another object of the present invention is to providepharmaceutical compositions containing such novel and valuablesubstituted phenylacetic acid compounds.

A further object of the present invention is to provide a method ofadministering such pharmaceutical compositions for theiranti-inflammatory, analgesic, and antipyretic activity.

Other objects and advantageous features of the present invention willbecome apparent as the description proceeds.

In principle the substituted phenylacetic acid compounds according tothe present invention are compounds of the following Formula I EQZLO3,825,587. Patented July 23, 1974 wherein R is cycloalkyl with 5 to 7carbon atoms in the cycloalkyl ring such as cyclohexyl, cyclopentyl,cycloheptyl; lower alkyl substituted cycloalkyl such as methylcyclopentyl, methylcyclohexyl; straight-chain or branched alkyl with lto 8 carbon atoms; phenyl; or phenyl substituted by trifiuoromethyl CFhalogen, lower alkylsulfonyl --S0 R, nitro, or cyano, such astrifluoromethylphenyl, chlorophenyl, methylsulfonylphenyl, nitrophenyl,cyanophenyl; 1

R is halogen such as chloro, bromo, iodo, fluoro; nitro; cyano;trifluoromethyl CF lower alkylsulfonyl -SO R, such as methylsulfonyl; orhydrogen, if R, is substituted phenyl;

R is hydrogen or lower alkyl with 1 to 8 carbon atoms such as methyl;

X is halogen such as chloro, bromo, iodo, fluoro; mercapto -SH; loweralkylmercapto SR; lower alkylsulfonyl SO R; thiocyano SCN; cyano;sulfonate -SO M, wherein M is a substantially nontoxic alkali metal;thiosulfate S O M; lower alkanoylthio -S.C.O.R; lower alkylxanthylisothioureido -S.CNH2;

NHzCl amino; lower, alkylamino -NHR and di- (lower alkyl) amino loweralkanoylamino NH.CO.R; the group of the formula and Y is hydroxyl; orthe amide group R! -N/ t wherein R and R" are hydrogen, lower alkyl,aralkyl, such as benzyl, or R and R together with the nitrogen atom towhich they are attached, form a heterocyclic ring, such as thepyrrolidino, piperidino, piperazino, or the like heterocyclic ring; andwherein X and Y together with the two carbon atoms to which they areattached, form a heterocyclic ring of the formula i. Thepresentinventioncomprises also the substantially won-toxic,pharmaceutically acceptable esters. and salts of the substitutedphenylacetic acids of Formula I wherein or a hetero'c 'yc licringbftheformula Y is hydroxyl. Such esters are, .for instance:

(a) the esters with lower aliphatic alcohols such as with methanol,ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-amyl alcohol,isobutylcarbinol, n-hexanol, n-heptanol, n-octanol, monomethylether ofethylene glycol, allyl alcohol, diethylaminoethanol, piperidinoethanol,piperazinoethanol, pyrrolidinoethanol, and other alcohols with 1 to 8carbon atoms;

,, (b) the esters with alicyclic alcohols and alcohols of the terpeneseries, such as with cyclopentanol, cyclohexanol, 2-methylcyclohexanol,cyclohexylcarbinol, menthol, .borneol, fenchyl alcohol, andotheralicyclic alcohols with 6 to 14 carbon atoms;

the esters with hydroxyl substituted aryl compounds such as with phenol,cresol, guajacol, and other phenolic compounds with 6 to 14 carbonatoms;

(d) the esters with aryl substituted alkanols such as benzyl alcohol,phenylethyl alcohol, anisalcohol, and other aryl substituted alkanolswith 7 to 14 carbon atoms;

(e) the esters with heterocyclic alcohols such as furfuralcohol andothers.

The lower alkyl esters are the preferred esters.

Suitable substantially non-toxic, pharamaceutically acceptable salts ofthe" substituted phenyl acetic acids of Formula I, wherein Y ishydroxyl, are, for instance, the alkali metal or alkaline earth metalsalts, such as the sodium, potassium, or calcium salts, the ammoniumsalts, or the salts with organic bases such as the di-loweralkylammonium salts, for instance, the dimethylammonium salt, thediethylammonium salt, the hydroxy lower alkylammonium salts such as theB-hydroxyethylammonium salt, the piperazinium salt, the piperidiniumsalt, the lower alkyl benzylammonium salts such as theu-methylbenzylammonium salt, and others.

The term lower alkyl as used herein and in the claims annexed heretodesignates straight-chain or branched alkyl with 1 to 8 carbon atoms.

In particular the substituted phenylacetic acid compounds of the presentinvention are (a) a-halophenylacetic acids of Formula II (c)'a-sulfur'derivatives of such a-mercaptophenylacetic acids of FormulaIVS-derivative such as the corresponding sulfides, disulfides,thiosulfates, xanthates, isothiuronium halides, oxothiazolidines, andthe like compounds which serve as latent forms or precursors of thea-mercaptophenylacetic acids of Formula II.

Not only the substituted-phenylacetic acids of Formulas 11 to IV butalso their non-toxic salts, the esters, and

the amides ot said substituted phenylacetic acids have proved to -beuseful'--anti=inflammatory;*antipyretic; and

analgesic agents and are used in reducing the inflammation and painassociated with polyarthritis in mammals.

The compounds of Formula I are administered preferably orally as theirnon-toxic "salts or esters in the form of powder, granules, capsules,coated or uncoat'ed compressed tablets, or as anaqueous suspension orsolution.

"They may also be administered"parenterallyasa'sterile aqueous solutionof their non-toiric salts, Compounds that are especially useful includethe a,m-dih alo-p-cycloalkyl phenylacetic acids, u,o'dihalo-p-biphenylylacetiq acids, a,m-dihalo-p-lower alkylphenylaceticacids. Theprefe'rred compounds of this invention area,m-dichloro-p-cyclohexylphenylacetic acid of FormulaV Cl Q- Cl itslower alkyl esters, and its non-toxic salts; they are administeredpreferably orally in a dose range of 0.1 mg. to 10 mg. per kg. of bodyweight. The acute oral toxicity of the preferred compounds arerelatively low.

The starting materials for producing the substituted ochalophenyl aceticacids according to Formula II are lower alkyl esters of thecorresponding substituted phenylglycolic acid in whcih R is lower alkyl(C to C8), cycloalkyl (C to Cq), phenyl, halophenyl, nitrophenyl,tr-ifluoromethylphenyl, cyanophenyl, or methylsulfonylphenyl; R ishydrogen or lower alkyl; Ris lower alkyl, and-R is halogen, nitro,cyano, trifluoromethyl, methylsulfonyl, or hydrogen (when R issubstituted phenyl). The substituted phenylglycolic acid lower alkylesters of Formula VII are prepared by the method disclosed in copendingpatent application Ser. No. 767,058 from the lower alkyl esters of thecorresponding substituted phenylglyoxylic acid of Formula VI either bycatalytic hydrogenation when R is hydrogen, or by reaction with a loweralkyl Grignard reagent when R is lower alkyl, as illustrated by thefollowing equation:

When R is nitro, it is preferable to reduce the lower alkyl ester ofFormula VII-I of the substituted m-nitrophenylglycolic acid with sodiumborohydride in methanol to obtain the corresponding lower alkyl ester ofFormula IX of a substituted m-nitrophenylglycolic acid. This procedureis illustrated by the following, equationi N 02 VIII Substitutedm-fiuorophenylglycolate esters of Formula XIII are also obtained bycatalytic hydrogenation'of the corresponding substitutedm-nitrophenylglycolate esters of Formula X to give the substitutedm-aminophenylglycolate esters of Formula XI which, after' conversion tothe diazonium fluoroborate of Formula X II are thermally decomposed tothe substituted m-fluorophenylglycolate,

5 esters of Formula XIII as shown in the following equations:

As stated above, the substituted phenylglyoxylic acid lower alkyl estersof Formula VI are produced according to the method of copending PatentApplication Ser. No. 767,058 by reacting an alkylbenzene, acycloalkylbenzene, or a biphenyl of Formula )GV with a lower alkyloxalyl chloride of Formula XV in the presence of aluminum chloride. Theresulting lower alkyl esters of the p-alkyl, p-cycloalkyl, ofp-biphenylylglyoxylic acids of Formula XVI may be halogenated accordingto the method described in said Patent Application Ser. No. 767,058, orthey may be nitrated with fuming nitric acid at about C. to producerespectively the corresponding lower alkyl esters of a substitutedm-halophenylglyoxylic acid of Formula XVH or a substitutedm-nitrophenylglyoxylic acid of Formula IX according to the followingequations:

0 O A1013 g R1 Cl COOR R1 COOR XVI halogen O i l-COOR XVI Additionalvariations in R are obtained by reacting a lower alkyl ester of asubstituted m-halophenylglyoxylic acid of Formula XVII as follows:

(a) with cuprous cyanide in quinoline at about 150 C.

to produce a lower alkyl ester of a substituted m-cyanophenylglyoxylicacid of Formula XVIII:

0 O I]; CuCN 1]: R1 COOR R1 COOR al N XVII

XVIII (b) with trifluoromethyliodide and copper powder at about 150 C.in dirnethylformamide to produce a lower alkyl ester of a substitutedm-trifluoromethylphenylglyoxylic acid of Formula XIX by following themethod described by Y. Kobayashi and I. Kumadaki in Tetrahedron Letters,vol. 47, p. 4095 (1959).

O 0 g CFaI g R: COOR --v R: COOR Cu XVII XIX 6 (c) with cuprousmethanesulfinate in quinoline at about 150 C. to produce a lower alkylester of a substituted m-methylsulfonylphenylglyoxylic acid of FormulaXX:

II CHSO CH; R C-CO OR XVII 1 R l-COOR The substituted phenylglycolicacid lower alkyl ester of Formula VII is reacted with a phosphorustrihalide, phosphorus pentahalide, phosphorus oxyhalide, sulfurylhalide,thionyl halide, or sulfur halide to produce a substituteda-halophenylacetic acid lower alkyl ester of Formula XXI in which Hal isF, Cl, Br, or I.

OH Hal R1 23-00011 R1 s-000R I, II; II 2 VII XXI The ester of FormulaXXI is heated with acetic acid containing the corresponding hydrogenhalide to give a substituted a-halophenylacetic acid of Formula II.

Hal

R1 E COOR R l-OOOH XXI II Hal Hal II XXII Reaction of the lower alkylester of a substituted u-halophenylacetic acid of Formula XXI withammonia or a lower alkylamine leads to a substituteda-halophenylacetamide of Formula XXIII in which -R is hydrogen or loweralkyl, and R is hydrogen or lower alkyl.

The substituted a-fluorophenylacetic acid derivatives of Formula XXV arealso obtained from the corresponding aiOdO, a-bromo, ora-chlorophenylacetic acid derivatives of Formula XXIVV by reaction withpotassium fluoride at about 200 C.

aaza s I Th z ubs u c -1. -hal p nxlacq a id iFo mt l II, their salts01:1 Formula XX'I I, or amides of Formula XXIII, or their lower alkylestersof Formula-)QiLm-ay be reacted with various'nucleophilic reagentsto replace the tat-halogen group. In i-particular sulf ur eontaining ,5nucleophilic reagents" 'are"u'sed such as alkali hydr'osulfides MSH,alkali sulfides M 5, alkali thio'lalkanoates MSCOR, alkali thiocyanatesMSCN, alkali sulfites M 80 alkali thiosulfates M 850 alkalialkanesulfinates I R: xxvr l Rl-Q--C 0 OM I R2 Reaction of a substtiuteda-halophenylacetic acid 49 derivative of the Formulas XXI, II, XXII, orXXIII with thiourea at elevatedtemperatures, for instance, in boilingethanol produces a S-substituted-2-imino-4-oxothiazolidine of FormulaXXVHI:

Hydrolysis of the imino compound of Formula XXVIII with hydrobromic acidin glacial acetic acid leads to a S-substituted-2,4-dioxothiazolidine ofFormula XXIX:

S NH Rr L =o g IMQWLLO R; Br

, R: R2 xxvnr xxrx 65 Hydrolysis of the imino compound of the FormulaXXVIII or the dioxothiazolidine of Formula XXIX with alkali hydroxide oralkali carbonate leads to a mixture of a substituteda-mercaptophenylacetic acid of Formula 70 XXVI and a'substitutcda,u-dithiodiacetic acidof Formula XXVII which "may be separated byfractional crystallization of their salts.

Reaction of a substituted a-halophenylacetic acid derivative of theFormulas XXI, XXIII, or II with thio- 75 -18 PIQGUQQSi iIaLIIISFIWWSIwise thioureidophenylacetic acid derivative of Formula XXX-z NgzHal :12'Ei G -NH vJ -thlourea .1

--- ooofl Reaction of a substituted a-halophenylacetic acid derivativeof the Formulas XXI, XXIII, II, or'XXII with an alkali loweralkylmercaptide produces a substituted a-lower alkylthiophenylaceticacid derivative of Formula XXXI in which R is a lower alkyl with 1 to 8"carbon atoms.

Reaction of a, substituted.a-halophenylacetic acid derivative of theFormula'SaXXI, II, XXIIgoriXXIII with an alkali lower alkylxanthate'produces a substituted aalkylxanthyl-phenylacetic acidderivative of the Formula XXXII in which R is loweralkyl Ofl'i to 8carbons: 5 1

m-Q-i-co 0M Reaction of a substituted a-halophenylacetic acid derivativeof the Formulas XXI, II, XXIII, or XXII with an alkali thioalkanoateproduces a substituted lower alkanoylthiophenylacetic acid of Formula)QCXIII in which R is a lower alkyl with I to 8 carbon atoms:

H81 soon 6 xsoon R1 -COOM--- R1 oooM xxrr fxxxirr Reaction of asubstituted a-halophe'nylacetic acid"de"- rivative of Formulas XXI, II,XXII, or XZXIIIiWith an alkali thiocyanate produces a substituteda-thioeyanophenylacetic acid derivative ,of Formula H81 3 UN 5 KS CN R;--C 0 0M 7, R1 e 2 R: II XXXIV';

Reaction of -a substituted ,u-halophenylacetic jacid "derivative ofFormula XXLII, XXII, =01 XXIII with-an alkalicyanide produces asubstituted a-cyanophenylacetic acid derivative of. Formula 'XXXV:

Reaction of a substituted a-halophenylacetic acid derivative of FormulasXXI, II, XXII, or'XXIII with an O B Q-ii-Co OH alkali sulfide produces asubstituted a,a'-thiodiacetic acid derivative of Formula XPQCVI:

Reaction ofa substituted a-halophenylacetic acid derivative ofFormulasXXI, II, XXII, 'or XXIII with an alkali; sulfite produces-a substituteda-sulfophenylacetic acid derivative of Formula XXXVII:

Reaction of a substituted (Jr-phenylacetic acid derivative of FormulasXXI, II, XXII, or )QGII with an alkali thiosulfate produces asubstituted a-thiosulfophenylacetic acid derivative of Formula XXXVIII:

Hal SSOsNfl Na2S2O E R |COOH R1 COM I i s XXII XXXVIII Reaction of asubstituted u-halophenylacetic acid derivative of Formulas XXI, I I,XXII, or XXIII with an alkali alkanesulfinate produces a substituteda-alkylsulfonylphenyl acetic acid derivative of Formula XXXIX, in whichR is lower alkyl.

NaSOzR Hal 121G -COOH A. B2

XXII

0 0 a NazCO g mQ- COOM R1 COOH I R2 XI XLI IMQ- JJ-COOM 2 I I:

XXXIX Formula XL with'hydroxylamine. v

NHz'

"-Q XLIII, XLII Dehydration of the substituted phenylglyoxylic acidoxime of Formula XLII'I with boiling aceticanhydride leads to asubstituted benzonitrile of Formula XLIV which, with a lower alkylGrignard reagent, produces a substituted phenyl alkyl ketone of FormulaXLV, in which 'R;, is lower alkyl. The latter compound with ammoniumchloride and sodium cyanide produces a cyano hydrin of Formula XLVIwhich, upon acid hydrolysis, yields a substituted u-aminophenylaceticacid of Formula XL, in which R is a lower alkyl.

NOH ACzO R1 COOH R N XLIII XLIV RMgHal The substituted phenylaceticacids of this invention and their carboxyl derivatives are racemic, andmay be resolved into their optical isomers by standard procedures.Preferably a substituted phenylacetic acid is reacted in alcoholic oracetone solution with an equivalent amount of an optically activeprimary, secondary, or tertiary amine such as cinchonidine, cinchonine,quinine, ephedrine, a-methylbenzylamine, secondary butylamine, secondaryamylamine, and others. The diastereomeric amine salts produced thereby,are separated by fractional crystallization, and each optically activesalt is hydrolyzed with dilute mineral acid to produce the dextro orlevo form, respectively, of the substituted phenylacetic acid.Alternatively, the lower alkyl ester of a substituted phenylacetic acidis reacted with an optically active primary or secondary amine such asephedrine, a-methylbenzylarnine, secondary butylamine, and others, toproduce a mixture of diastereomeric substituted phenylacetarnides whichare separated by fractional crystallization. Each optically activephenylacetamide may be hydrolyzed with mineral acid to its respectiveoptically active substituted phenylacetic acid.

Examples of compounds according to the present invention which, however,is not limited thereto, are:

l. a,m-Dichloro-p-cyclohexylphenylacetic acid 2.a,m-Dichloro-p-cyclohexylphenylacetic acid, sodium salt 2a.a,m-Dichloro-p-cyclohexylphenylacetic acid, diethylammonium salt 3.u,m-Dichloro-p-cyclohexylphenylacetic acid, ethyl ester 4.a,m-Dichloro-p-cyclohexylphenylacetamide 5.a,m-Dichloro-p-cyclohexyl-N-isopropylphenylacetamide 6.a,m-Dichloro-p-cyclohexyl-a-methylphenylacetic acid 7.a-Bromo-m-chloro-p-cyclohexylphenylacetic acid 8.m-Bromo-a-chloro-p-cyclohexylphenylacetic acid9.1-m-Chloro-p-cyclohexyl-a-mercaptophenylacetic acid 10. m-chlorop-cyclohexyl-a-acetomercaptophcnylaoetic acid I i 1'1.m-Chloro-p-cyclohexyl-a-methylmercaptophenyL acetic acid 12.m-Chloro-p-cyclohexyl-a-methylsulionylphenyl i acetic acid I 13-.m-Chloro-p-cyclohexyl-a-thiocyanophenylacetic acid 1 14.-rn-Chloro-p-cyclohexyl-a-aminophenylacetic acid 15. .m-Chloro-pcyclohexyl-a-acetaminophenylacetic' acid 16. a,a'-Di-(m-chloro-p-cyclohexylphenyl) -a,oz'-ditbi0- diacetic acid 17.a-Chloro-p-cyclohexyl-m-nitrophenylacetic acid 18.a-Chloro-m-cyano-p-cyclohexylphenylacetic acid 19.a-Chloro-p-cyclohexyl-m-trifluoromethylphenylacetic acid 20.a,m-Dichloro-p-cyclopentylphenylacetic acid 21.a,m-Dichloro-p-cycloheptylphenylacetic acid 22.5-(m-Chloro-p-cyclohexylphenyl)-2,4-dioxothiazolidine 23.5-(m-Chloro-p-cyclohexylphenyl)-5-methy1-2- irnino-4-oxothiazolidine 24.-2-(ni-Chloro-p-cyclohexylphenyl)-2-imino-4- oxothiazolidine 25.a,u"-Di-(m-chloro-p-cyclohexylphenyl)-a,u'-thiodiacetic acid 26.a0-Dichl0ro-p-biphenylacetic acid 27.a,m-Dichloro-p-isobutylphenylacetic acid 28.m-Chloro-p-cyclohexyl-a-sulfophenylacetic acid,

sodium salt 29. m-Chloro-p-cyclohexyl-a-thiosulfophenylacetic acid,

sodium salt 30. m-Chloro-p-cyclohexyl-u-cyanophenylacetic acid,

sodium salt 31. m-Chloro-p-cyclohexyl-a-ethylxanthylphenylacetic acid,ethyl ester 32. o- Bromo-a-chloro-p-biphenylacetic acid 33.a,m-Dichloro-p-sec.-amylphenylacetic acid 34.a-Chloro-o-trifluoromethyl-p-biphenylacetic acid 35.u-Chloro-o'-nitro-p-biphenylacetic acid 36.a-Ch1oro-o'-cyano-p-biphenylacetic acid 37.m-Chloro-p-cyclohexyl-wfluorophenylacetic acid 38.0'-Chloro-a-mercapto-p-biphenylacetic acid 39.m-Chloro-p-isobutyl-a-mercaptophenylacetic acid 40.a,m-Dichloro-p-cyclohexylphcnylacetic acid, benzyl ester 41.a,rn-Dichloro-p-cyclohexylphenylacetic acid,

ester 42. a,m-Dichloro-p-cyclohexylphenylacetic acid,

hexyl ester 43. a,m-Dichloro-p-cyclohexylphenylacetic acid,

ester 44. a,m-Dichloro-p-cyclohexylphenylacetic acid,

aminoethyl ester 45. a,m-Dichloro-p-cyclohexy1phenylacetic acid,

dinoethyl ester.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The following examples serve toillustrate the present invention without, however, limiting the samethereto.

EXAMPLE 1 a,m-Dichloro-p-cyclohexylphenylacetic acid ethyl ester 221.7:g. (0.747 mole) of the ethyl ester of m-chlorop-cyclohexylphenylglycolicacid are stirred with 106.67- g. (0.895 mole) of thionylchloride. atroom temperature for 24 hours and then heated to reflux for 6 hours. Thecold reaction. mixture is poured into 1125ml. of ice-cold water withstirring. The mixture is extracted with. 800ml. of ether; The etherealsolution is washed with-45 ml. of. cold saturated sodium hydrocarbonatesolution-followed by washing twice, each time'with 250. ml. of coldwater; The ethereal-solution is dried over: anhydrous sodium sulfate andfiltered. The solvent is removed by distillation.

menthyl cyclophenyl diethyl- 12 under reduced pressure. Yield: 230.7 g.(97.9%) liquid, hp. 118-122 C./0.0-5 mm. Hg.

T .L.C. (silica): 5C H :4HCOOET:1 HCOOH, R =0.86, 0.70 (trace). Anal.Calculated for CwHzgClgOgZ 60.96% C; 6.40% H;

22.49% Cl. Found: 60.96% C; 6.46% H; 21.56% Cl.

EXAMPLE 2 a,m-Dichloro-p-cyclohxylphenylacetic acid TLC (silica): 50,11,;4 'HCOOEtzl ncoon, R,.'=0.'64,

0.49 (trace).

EXAMPLE 3 a,m-Dichloro-p-cyclohexylphenylacetic acid sodium salt Asolution of 12.4 g. of sodium bicarbonate in'"135 ml. H O is addeddropwise to a stirred solution of 47.1 g. (0.164 moles) ofann-dichloro-p-cyclohexylphenylacetic acid in 150 cc. of methanol. Thesolvent is removed in vacuum, and the residue is dried by repeateddistillations with anhydrous ethanoL'The crystalline residue istriturated with ether cc.), collected on a filter, and washed withether. After drying in a vac'cum desiccator overnight, the crystallineproduct weighs 41.6 g. (91.3%).

I of

TLC (silica): s c,H,:4 HCOOEt:1 rrcoon, RF=0.62,

0.49 (trace).

Anal. Calculated for C H Cl O Na: 54.38% C; 4.89%

H; 22.93% Cl. Found 54.10% C; 5.18% H; 21.75% Cl.

EXAMPLE 4 Diethylammonium salt of u,m-dichloro-p-cyclohexylphenylaceticacid Anhydrous diethylamine (0.11 moles) is added dropwise to a stirredsolution of a,m-dichloro-p-cyclohexylphenylacetic acid (0.10 moles) in100 ml. of n-hexane at 0 C. The preciiptated diethylammonium .salt iscol-,.

lected on a filter, washed with n-hexane, and dried in a vacuumdesiccator.

Yield: 34 g., white crystals, M.P. 109-115 C.

Anal. Calculated for C H Cl NO 60.00% C; 7.55%

H; 3.89% N, 19.68% CL'Found: 60.23 H;'-3'.79%'N; 19.24% Cl.

a,m-Dichloro-p cyclohexyl N-isopropylplienylacetamide 5 g. (0.016 moles)of the ethyl ester of oam-dichloro-p- "cyclohexylphenylacetic acid arestirred with 5.5 ml. of

XAMP a-Bromo-m-chloro-p-cyclohexylphenylaeetic acid ethyl sf \"T; f e tTo 15.0 g. (0.0476 moles) of m-chloro-p-cyclohexylphenylglycolic acidethyl ester there are added slowly with stirring at 40-50 C. 23 g.(0.053 moles) of phosphorus pentabromide. The mixture is stirred at roomtemperature for 16 hours, then diluted with 70 ml. of petroleum ether,and poured into 125 ml. of ice-cold water. The organic phase isseparated, washed with saturated aqueous sodium hydrogen carbonatesolution, dried over anhydrous sodium sulfate, filtered and the solventremoved in vacuo to leave 12.1 g. (70.8%) of crude product. Distillationof the residue gives 8.1 g. (47.4%) of a pale yellow liquid, b.p.157-161 C./0.10 mm. Hg.

TLC (silica): 5 C H :4 HCOOEt:1 HCOOH, R =0.90

Anal. Calculated for C H BrC1O:

Calculated: 53.42% C; 5.60% H; 32.08% Cl-l-Br Found: 53.42% C; 5.42% H;31.6% Cl-l-Br EXAMPLE 7 Diethylammonium salt ofa-bromo-m-chloro-p-cyclohexylphenylacetic acid The salt is prepared froma-bromo-m-chloro-p-eyclohexylphenylacetic acid ethyl ester by treatingthe same with glacial acetic acid and 48% hydrobromic acid, andconversion to the diethylammonium salt with diethylamine in an analogousmanner as described in Examples 68.4 g. (0.330 moles) of phosphoruspentachloride are slowly added with stirring to 92.4 g. (0.300 moles) ofmchloro p cyclohexyl-a-methylphenylglycolic acid ethyl ester. Themixture is allowed to warm spontaneously and is stirred at roomtemperature for ,16 hours. The cold reaction mixture is diluted with 340ml. of petroleum ether and stirred with 500 ml. of ice water. Theorganic phase is separated and is then washed with cold 10% sodiumbicarbonate solution (twice with 90 ml. each time) followed 'by a waterwash. The organic phase is dried over sodium sulfate, filtered, and thesolvent is removed under reduced pressure to give 86.3 g. (87.5%) of theabove ester, b.p. 155158 C./0.35 mm. Hg.

14 TLC (silica): 5 C H :4 HCOOEt:1 HCOOH, R =0.90,

0.71 (trace) Anal. Calculated for C H Cl O 62.00% C; 6.73% H; 21.53% Cl.Found: 62.92% C; 6.43% H; 21.62% C].

EXAMPLE 9 Sodium salt of u-chloro-m-nitro-p-cyclohexylphenylacetic acidThe salt is prepared in the same manner as described Example 3 exceptthat the starting material is m-nitro-pcyclohexylphenylglycolic acidethyl ester. The latter is obtained by nitration ofp-cyclohexylphenylglyoxylic acid ethyl ester with fuming nitric acid at0 C. and reduction with sodium borohydride.

EXAMPLE 10 Sodium salt ofa-chloro-m-trifluoromethyl-p-cyclohexylphenylacetic acid 01 OQJJHCOOM:

EXAMPLE 11 The sodium salt of a-chloro-m-cyano-p-cyclohexylphenylaceticacid The salt is prepared in the same manner as described in Example 3except that the starting material is m-cyano-pcyclohexylphenylglycolicacid ethyl ester. The latter is obtained from the corresponding mbromo-p-cyclohexylphenylglyoxylate ester with cuprous cyanide inquinoline at about C., followed by catalytic hydrogenation over platinumat 25 C. and 3 atm. pressure.

EXAMPLE 12 Sodium salt of u,o-dichloro-p-phenylylacetic acid The salt isprepared in the same manner as described in Example 3 except that thestarting material is o'-chIoro-p-biphenylylglycolic acid ethyl ester.

EXAMPLE 13 Sodium salt of o'-bromo-a-chloropbiphenylylacetic acid@Q-dnooom I Br The salt is prepared in the same manner as described inExample 3 except that the starting material is'o'-bromo-p-biphenylylglycolio acid ethyl ester.

3,825, 15 V EXAMPLE 14 Sodium salt ofa,m-dichloro-p-isobutylphenylacetic acid (CHahOHCH -Q-CHC o 0 Na Thesalt is prepared in the same manner as described in Example 3 exceptthat the starting material is m-chlor0-p-isobutylphenylglycolic acidethyl ester.

EXAMPLE 15 Sodium salt of a-chloro-d-trifluoromethylp-biphenylylaceticacid EXAMPLE 16 5- (m-Chloro-p-cyclohexylphenyl)-2-imino-4-oxothiazolidine 230.7 g. (0.732 moles) of the ethyl ester of cm-dichloro-p-cyclohexylphenyl acetic acid are dissolved in 9 60 ml. ofethanol. To this solution there are added 66.9 g. (0.878 moles) ofthiourea. The mixture is heated under reflux with stirring for 26 hours,whereupon the product precipitates out. The cold reaction mixture isdiluted with 2.3 1. of water. The light yellow solid is collected on afilter and washed with 20% ethanol. The product is dried at 60 C. in avacuum to remove most of the water, then stirred with 2 l. of anhydrousether, collected by filtration, washed with anhydrous ether, and driedat 60 C. in a-vacuum. Yield: 145.2 g. (64.3%), m.p. 240-242 C.

TLC(silica): 5 toluene:4 HCOOEtzl HCOOH, R =0.44 A'nal. Calculated for CH ClNOS: 58.24% C; 5.55% H; 9.07% N; 11.48% Cl; 10.38%. Found: 58.09% C5.49% H; 8.22% N; 12.09% Cl;l0.08% S EXAMPLE 175-[m-Chloro-p-cyclohexylphenyl] -2,4-dioxothiazolidin e 1 l lH y ll I15.44 g. (0.05 moles) of- 5-(nrchlorop-cyclohexylphenyl)-2-imino-4-oxothiazolidine are refluxed with 200 ml.of 48% hydrobromic acid with stirring for 24 hours. The hydrobromic acidis removed by distillation under reduced pressure. The residue isextracted with ether. The etheral solution is washed with water anddried over anhydrous magnesium sulfate. After removing the drying agentand the solvent, the residue is triturated'with n-" hexane. The whitesolid which separates is. collected by- 181.8'g. 0.427 moles) of 5-[mchloro-pwyclbhexylphenyl]-2-imino-4-oxothiazolidine; '1- liter of-10%:jsddi" hydroxide solution, and 325 m1. of=% ethanola're -'re'fluxed with stirring for 20 hours."After"distilling "bti 'thei ethanol,the mixture is cooled to-"room 'temperatur'e'yi washed three times withether, each time 'with"300 mli-fE of ether, and acidified with 310ml.of'-6N'-hydrochlori'c* acid solution (1.86 moles) with stirring in-th'epresence of 700 ml. of ether. The aqueous portion is extracted twicewith ether, each time with 400ml. ofetherfffllie combined etherealsolution is dried over anhydrous mag nesium sulfate and filtered. Thesolvent is removed unde reduced pressure leaving the above acid.

EXAMPLE 19 Diethylammonium salt of a,a'-di-[ rn'-chloro'-'pcyclohexylphenyl];-a,a'*dithiodiacetic acid 113 g. (0.199 moles) ofcrude c,u='-di-[m-chloro p 'cw' clohexylphenyl]-u,a-dithiodiacetic acidare'dissolved in" 800 ml. of anhydrous ether. To this solution there-areadded dropwise with stirring 33.2 .g.- (-0.454 moles) of diethylaminediluted with 30 ml. of anhydrous ether. The mixture is stirred for 3hours, whereupon the crude product precipitates out. The solid iscollected on a filter and... washed with anhydrous ether. The"crudepr'oduct is 'r'e-"' crystallized from chloroform/ethyl"acetate;Yield: 37.8 g. (26.6%) white solid, M.P. 136- 1 38 C..

Diethylammonium"?salt jofj h I -saaa ha The chloroform ethylacetatfiltrate" fro Example 9 i evaporated to dryness in vacuo," a'rid 'th'rsidue is tritu- 1 7 rated with ether to precipitate the above salt, 103109 C.

m-Chloro-p-cyclohexyl u mercaptophenylacetic acid is also obtained byreducing a,a-di-(m-chloro-p-cyclohexyl)-u,a'-dithioacetic acid with zincamalgam and dilute sulfuric acid, or by reacting the sodium salt of tm-dichloro-p-cyclohexylphenylacetic acid with excess aqueousalcoholicsodium hydrosulfide under a nitrogen atmosphere, and separating themercaptan from the disulfide by fractional crystallization of thediethylammonium salts.

EXAMPLE 21 -(m-Chloro-p-cyclohexylphenyl)-2-imino-5-methyl-4-oxothiazolidine CH3 m \C/NH TLC (silica): 5 C A-1 :4 HCOOEt:1HCOOH, R =0.51 Anal. Calculated for C H ClN OS: 59.52% C; 5.93%

H; 10.98%C1; 9.93% S; 8.68% N. Found: 59.34% C; 6.30% H; 10.98% Cl;10.67% S; 8.44% N EXAMPLE 22 Sodium salt ofm-chloro-p-cyclohexyla-acetothiophenyl acid SCOCH:

The sodium salt of a,m-dichloro-p-cyclohexylphenylacetic acid (0.050moles) is reacted with purified sodium thioacetate (0.050 moles) in 100ml. of anhydrous ethanol' at 25-80" C. under a nitrogen atmosphere for 4to 8 hours. The precipitated sodium chloride is filtered oil and thefiltrate'is concentrated to dryness in vacuo at 25 C. to leave the crudeproduct as a residue. The latter is purified by recrystallization or bycolumn chromatography.

EXAMPLE 23 Sodium salt of m-chloro-p-cyclohexylu-methylthiophenylaceticacid S OH:

The procedure is the same as described in Example 22 except that sodiummethanesulfinate is used in place of v I 7 thiolacetate.

sodium thiolacetate.

1s EXAMPLE '24 Sodium salt ofm-chloro-p-cyclohexyla-methylsulfonylphenylacetic acid s 802cm Theprocedure is the same as described in Example 22 except that sodiummethanesulfinate is used-in place of sodium thiolacetate.

EXAMPLE 25 Sodium salt of m-chloro-p-cyclohexylu-thiocyanophenylaceticacid @QJJHCOONB.

The procedure is the same as described in Example 22 except that sodiumthiocyanate is used in place of sodium thiolacetate.

EXAMPLE 26 Sodium salt of rn-chloro-p-cyclohexyla-sulfophenylacetic acidS OaNB OQdncoom The procedure is the same as described in Example 22except that sodium sulfite is used in place of sodium thiolacetate.

EXAMPLE 27 Sodium salt of m-chloro-p-cyclohexyla-thiosulfophenylaceticacid r SSO Na @Qimcoom The procedure is the same as described in Example22 except that sodium thiosulfate is used in place of sodiumthiolacetate.

EXAMPLE 28 Sodium salt ofm-chloro-p-cyclohexyl-a-ethylxanthylphenylacetic acid S S 1 10 C311;

O-Q-dncoom The procedure is the same as described in Example 22 exceptthat sodium ethyl Xanthate is used in place of sodium thiolacetate.

EXAMPLE 29 Sodium salt of m-chloro-p-cyclohexyl-u-cyanophenylacetic acidON O-Q-cmwm t1 The procedure is the same as described in Example 22,

except that sodium cyanide is usedin place of sodium The procedure isthe same as described in Example 22, except that sodium sulfide (0.025moles) is used in place of sodium thiolacetate (0.050 moles).

EXAMPLE 31 Hydrochloride ofm-chloro-p-cyclohexyl-ot-isothioureidophenylacetic, acid NHzCl S CNH:

OQ-tmooon The procedure is the same as described in Example 22, exceptthat thiourea is used in place of sodium thiolacetate, and the reactionis conducted at C. with a,m-dichloro-p-cyclohexylphenylacetic acid(rather than with its sodium salt).

EXAMPLE 32 m-Chloro-p-cyclohexylphenylglyoxylic acid oximem-Chloro-p-cyclohexylphenylglyoxylic acid ethyl ester is hydrolyzed byheating with a 10% sodium carbonate solution for 24 hours. The coldreaction mixture is washed with ether, acidified with cold dilutehydrochloric acid, and extracted with ether. Removal of the ether leavesthe carboxylic acid compound. 38.5 g. (0.144 moles) ofmchloro-p-cyclohexylphenylglyoxylic acid, 37.0 g. (0.45 moles) of sodiumacetate, and 16 g. (0.23 moles) of hydroxylamine hydrochloride arestirred in 300 ml. of 50% aqueous ethanol at room temperature for 24hours. The mixture is diluted with water, brought to a pH of 4.0 by theaddition of hydrochloric acid, and extracted three times with ether. Thecombined ether extracts are dried over anhydrous magnesium sulfate,filtered, and'concentrated under reduced pressure. On trituration withcyclohexane, 12 g. (29 /270) of the oxime are obtained, M.P. 169.5 C.with decomposition. The oxime :gives a red coloration with ferricchloride solution. On concentrating the filtrate and adding heptane, anadditional amount of the oxime is obtained, 17.3 g. (42.5%); totalcombined yield: 29.3 g. (72%).

TLC (silica): 5 C H :4 HCOOEt:1 HCOOH, R =0.46

Analysin'Calculated for C H ClNO 59.68% C; 5.72%

H; 12.59% Cl; 4.97% N. Found: 60.10% C; 5.80% H; 11.88% Cl; 4.89% N.

EXAMPLE 33 mAminom-chloro-p-cyclohexylphenylacetic acid 'NOH 17.8 g.(0.06 33 moles) of m-chloro-p-cyclohexylphenylglyoxylic acid oxime aredissolved in ml. of methanol. Platinum oxide catalyst (0.5 g.) and 12ml. of 6N hydrochloric acid (0.072 moles) are added, and the mixture isshaken with hydrogen at an initial pressure of 55 p.s.i. Total uptake is98% of theory in 4 hours. The catalyst is filtered off and the solventis distilled ofi under reducedv pressure. The residue is triturated withwater containing 5.9 g. (0.072 moles) of sodium acetate, filtered, andWashed several times with water. The precipitate is stirred withanhydrous ether, filtered, and washed with ether.

Yield: 15 g. (89%), M.P. 204-205 C. with decomposition.

Analysis: Calculated for C H ClNO /:HCl: 58.79% C; 6.52% H; 18.60% Cl;4.90% N. Found: 59.52% C; 6.55% H; 18.67% Cl; 4.94% N.

Pharmaceutical Compositions Containing the Compounds According to thePresent Invention The novel substituted phenylacetic acid compoundsaccording to the present invention are preferably 'administered intherapy in the form of orally administrable solid shaped preparationssuch as tablets, dragees which may be enterically coated, pills,lozenges, orfin powder orgranule form, preferably enclosed in gelatinand the like capsules. Administration in liquid form, such as in theform of solutions, sirups, emulsions, suspensions,dispersions, fruitjuices and the like is also possible. I

Such powders, granules, and mixtures to'be used in the preparations oftablets and other shaped and/or compressed preparations may be dilutedby mixing and milling with a solid pulverulent extending agent to thedesired degree of fineness or by impregnating the already milled, finelypowdered, solid carrier with a suspension of said compounds in water orwith a solution'thereof in an organic solvent such as ethanol, methanol,acetone, and others and then removing the Wateror solvent.

When preparing tablets, pills, dragees, and the like shaped and/orcompressed preparations, the commonly used diluting, binding, anddisintegrating agents, lubricants, and other tableting adjuvants areemployed, 'provided they are compatible with said substitutedphenylacetic acid compounds. Such diluting agents and other excipientsare, for instance, sugar, lactose, levulose, starch, bolus alba; asdisintegrating and binding agents, gelatin,

gum arabic, yeast extract, agar, tragacanth,'methyl cellu-' lose,pectin; and as lubricants stearic acid, talc, magne-' sium stearate, andothers.

The compounds according to Formula I may also be are intimatelymixed'wi'th each 'other Portions-of 200 mg. each of -said mixture arefilled into soft gelatin capsules. Each gelatin capsule thus contains 25mg. of the active substituted 'phenylacetic acid ester .of thisinvention.

7 EXAMPLE 35 100 g; of the diethylammonium salt ofa,m-dichloro-pcyclohexylphenylacetic acid; a v

1200 g. of starch (direct compression grade) as sold by the firm A. E.Staley Mfg. Co. of Decatur, 111., under v the trademark Starex, and

g. of magnesium stearate are thoroughly blended and compressed to givetablets, each containing 25 mg. of the active ingredient.

EXAMPLE 36 The mixture of Example 35 is compressed to biconcave drageecores, each containing 25 mg. of the active ingredient. The cores arethen provided in a manner known in the compounding art with an entericshellac coating.

Of course, other dosage forms than capsules and tablets can be preparedby using well known compounding techniques and thea,m-dichloro-p-cyclohexylphenylacetic acid compounds used in Examples 34to 36 can be replaced by other substituted phenylacetic acid compoundsaccording to the present invention.

7 Pharmacological Tests A brief description of the pharmacological testsconducted With the compounds according to the present invention aregiven below:

Carrageenan Paw Edema.-Of the substances used to induce .loca'lirritation, carrageenan was selected since most known non-steroidalanti-inflammatory agents inhibit this inflammation. v

Ten male rats per dose group (120-150 g.) were given one-half of thetest material orally. Thirty minutes later, the remainder of the dosewas given and 0.2 ml. of a 1% carrag'eenan (solution was injectedsubdermally into the plantar surface of the hind paw. Each paw is markedas a consistent anatomical site, then immersed in a mercury bath to thatpoint. The mercury bath is connected to a pressure transducer and thevolume of displacement is read directly on a recorder. Three hours afterdrug administration, the hind paw volume is measured again. Theincreased volume is an index of edema. Treated groups are compared to aplacebo-treated group to calculate the percent inhibition of edema.

Filter Paper Granuloma.This assay was used to evaluate anti-inflammatoryagents and to determine the lowest dose which produces significantinhibition of granuloma growth. This assay has the advantage of beingsemiacute (4 to 7 days). The usual end point involves obtaining thewetweight as well as the dry weight of the granuloma.

Small discs of filter paper saturated with carrageenan were placedsubcutaneously in each rat on the first day of the study. Test compoundwas administered orally on a b.i.d. basis on Day 1 to Day 4. On Day 5, asingle dose was given in the morning and the animals were sacrificed inthe afternoon. Both filter paper discs were removed andtrimmed ofextraneous tissue and then weighed. After drying in an oven over theweekend, the dry weight was obtained. Activity was determined by thedifference in granuloma weight between a placebo-treated control groupand the drug-treated groups.

Randall-Selitto Analgesia Test.In accordancev with the Randall-Selittotest for measuring the pain threshold,

22 the pressure needed on a metal plunger to give a pain reponse in arat when the plunger is placed in the yeastinfiamed hind paw of a rat ismeasured. Following measurement of control pain threshold, yeast wasinjected into the paw" and the test compound was given orally.

The pain threshold was measured at hourly intervals and compared to aplacebo-treated control group.

Anti-Pyretic Assay.Brewers yeast'was injected subcutaneously in rats andrectal temperatures were obtained at the end of five hours. Those rats(10 per group) having a significant fever were given test compounds andrectal temperatures were measured at hourly intervals for 2 to 3 hours.(A positive response occurs when rectal temperature decreases by. 1 C.or more.)

Phenylquinone Analgesia.Mice were pre-treated orally with test compoundand then given 1.25 mg./kg. of phenylquinone i.p. to produce a series ofwrithes (severe intestinal contractions). The number of writhes wasrecorded. The percent decrease was calculated from the incidence ofwrithes in a placebo-treated control group.

Ultra-violet Erythema in Guinea Pigs.-Erythema associated withinflammation was used in the assay. Re-

stricted areas of a guinea pig were exposed to a controlled ultra-violetlight and after two hours the exposed areas were graded for the extentof erythema.

Polyarthritis in Rats.Twelve rats per dose group were treated (b.i.d.)starting the day before injection of adjuvant. Paw volumes were measuredfor both hind paws on several days during and following drug treatment.Drug was given for a period of 15 days. The paw volume was compared toan untreated control group to determine volume increase. Drug action wascalculated as the percent decrease in paw volume (inflammation) ascompared to an adjuvant-treated control. Gross signs of inflammationwere scored on a weekly basis and drug action calculated as a decreasein total score. Body weights were recorded at intervals.

Acute Toxicity.-Groups of ten (10) male mice (18 g. to 24 g.) weretreated with various does of drug and were observed for nine daysfollowing drug administration. Food and water were delivered ad lib. Thedrug to be tested was prepared as a water suspension using one drop ofTween per 10 ml. and administered orally as a single dose (10 ml./kg.).The control group received the vehicle only (10 ml./kg.). The lethaldose (LD which is the dose of drug required to kill 50 percent of theanimals tested, was determined by the Litchfield and Wilcoxon method.

The following compounds were tested:

Sodium salt of u,m-dichloro p cyclohexylphenylacetic acid, designated as539A;

Diethylammonium salt of m-chloro p cychlohexyl-amercaptophenylaceticacid, designated as 528A;

Diethylammonium salt ofa,a'-di-(m-chloro-p-cyclohexylphenyl)-a',ot'-dithiodiacetic acid,designated as 531A;

5-(m-Chloro-p-cyclohexylphenyl) 2 imino-4-oxothiazolidine, designated as530;

5 (m-Chloro-p-cyclohexylphenyl)-2,4-dioxothiazolidine,

designated as 529;

a,m-Dichloro p cyclohexylphenylacetic acid ethyl ester,

designated as 541.

The test results are given in the following Table wherein the followinglegends were employed:

PQW Phenylquinone Writhing. RSA Randall-Selitto Analgesia. CPECarrageenan Paw Edema. UVE Ultra-Violet Erythema. FPG Filter PaperGranuloma. AP Anti-Pyresis.

P.T. Pain Threshold. #P/T Number Positive/Total. %'r PercentageIncrease.

%J, Percentage Inhibition.

Polyarthritis, percent avg. inhibition at.1ng./kg./day FRG-atmg/r VkgJday Acute V 1 Nonin- Secondtoxicity Com- Dose PQW. OPE RSA AP UVEInjected jeeted ary %1. %1, (LD p ound mg./kg. Route 4 %t EDso %l T PT#P/T #P/T EDso hindpaw hindpaw lesions 'wet' dry mg.'/kg.o

539A 1 P.O.

2 P.O. 3. 125 P.O. 6

5 P.O. 6.25 P.O. 430 10 P.O. 14.1 28.2 12.5 P.O.

2O P.O. P.O. 12. 1 44.0 31.7 41. 1

3O P.O. 50 P.O. 59.6-51.2 39. 330.1 43.9 38.8 100 P.O.

528A 5 P.O. 10 P.O. 25 P.O. 50 P.O. 100 P.O. 35.6 34.0

531A 50 P.O. 32 1/8 l 100 P.O. 19. 9 28 1/8 34. 0-35. 6 44. 7-43. 8 30.H3. 6 2000 200 P.O. 51 6/8 l I Y 50 P.O. I 530 100 P.O. 51. 4 38.1 44. 717. 3 200 P.O.

2 50 P.O. 17.4 5 9 100 P.O. 1/8 42.0 17.3 21.0

25 P.O. 49. 8 50 P.O. 52.2

Clinical Utility The compounds of Formula I, their esters, and theirsalts have proved to be potent anti-inflammatory drugs with a highanalgesic and antipyretic activity. They are administered to patientssuffering from rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, acute gouty arthritis, bursitis, and other arthriticdisorders. The esters of said compounds and especially the ethyl esterof a,m-di- ,chlorocyclohexylphenylacetic acid have proved to beespecially useful as they are better tolerated and not as irritating onthe gastrointestinal tract as the free acids.

As stated hereinabove, the compounds of Formula I, their esters, andtheir salts are preferably administered in a dose of 0.1 mg./kg. to 10mg./kg. given once to four times daily. Thus the actual dose may varybetween about 5 mg. and about 500 mg. once to four times daily whichdose is preferably administered orally.

As stated hereinabove, the starting materials, i.e. the lower alkylesters of substituted phenylglycolic acids as well as of substitutedphenylglyoxylic acids are prepared according to processes described incopending application Ser. No. 767,058 of one of the Applicants of thepresent application, which application was filed Oct. 10, 1968 under thetitle "p-Cycloalkylphenylglycolic Acid and Derivatives Thereof. Saidapplication Ser. No. 767,058 and its contents thus are incorporated byreference into the present application.

UNITED STATES PATENTS 3,435,075 3/1969 Glamkowski spawn 260-590 OTHERREFERENCES I Reeve et a1., Journ. Am. Chem. .Soc., .vol. 89, No.. 3, pp.647-651 (1967). a

Bonner, J. Org. Chem.', vol. 33, No. 5, pp..1831 1836 (1968). t

LEON ZITVER, Primary E xaminer M. W. GLYNN, Assistant Examiner s. c1.X.R. I I

260-141, 268 C, 293.73 306.7, 326.82, 326.84, 454, 455 R, B, 465 E, 465F, 470, 471 C, 473 A, 476, 501.12, 502.6, 507 R, 518 R, 518 A, 519, 558RS, 559 R; 424 270, 301, 308, 309, 316, 317, 324 i

